Sex differences in glutamate transmission and plasticity in reward related regions.

Disruptions in glutamate homeostasis within the mesolimbic reward circuitry may play a role in the pathophysiology of various reward related disorders such as major depressive disorders, anxiety, and substance use disorders. Clear sex differences have emerged in the rates and symptom severity of these disorders which may result from differing underlying mechanisms of glutamatergic signaling. Indeed, preclinical models have begun to uncover baseline sex differences throughout the brain in glutamate transmission and synaptic plasticity. Glutamatergic synaptic strength can be assessed by looking at morphological features of glutamatergic neurons including spine size, spine density, and dendritic branching. Likewise, electrophysiology studies evaluate properties of glutamatergic neurons to provide information of their functional capacity. In combination with measures of glutamatergic transmission, synaptic plasticity can be evaluated using protocols that induce long-term potentiation or long-term depression. This review will consider preclinical rodent literature directly comparing glutamatergic transmission and plasticity in reward related regions of males and females. Additionally, we will suggest which regions are exhibiting evidence for sexually dimorphic mechanisms, convergent mechanisms, or no sex differences in glutamatergic transmission and plasticity and highlight gaps in the literature for future investigation.

The effect of traumatic brain injury on learning and memory: A synaptic focus.

Deficits in learning and memory are some of the most commonly reported symptoms following a traumatic brain injury (TBI). We will examine whether the neural basis of these deficits stems from alterations to bidirectional synaptic plasticity within the hippocampus. Although the CA1 subregion of the hippocampus has been a focus of TBI research, the dentate gyrus should also be given attention as it exhibits a unique ability for adult neurogenesis, a process highly susceptible to TBI-induced damage. This review examines our current understanding of how TBI results in deficits in synaptic plasticity, as well as how TBI-induced changes in endocannabinoid (eCB) systems may drive these changes. Through the synthesis and amalgamation of existing data, we propose a possible mechanism for eCB-mediated recovery in synaptic plasticity deficits. This hypothesis is based on the plausible roles of CB1 receptors in regulating inhibitory tone, influencing astrocytes and microglia, and modulating glutamate release. Dysregulation of the eCBs may be responsible for deficits in synaptic plasticity and learning following TBI. Taken together, the existing evidence indicates eCBs may contribute to TBI manifestation, pathogenesis, and recovery, but it also suggests there may be a therapeutic role for the eCB system in TBI.

GnRH protective effects against long-term potentiation impairment induced by AANAT-siRNA.

There is an interplay between the gonadotropin-releasing hormone (GnRH) and melatoninergic systems. The key enzyme of melatonin synthesis (arylalkylamine N-acetyltransferase, AANAT), and GnRH receptors are expressed in the hippocampus. While it has been shown that hippocampal AANAT enzyme activity is necessary for proper hippocampal cognitive function, their role in long-term potentiation (LTP) induction is not fully understood. In current study, the impact of GnRH on LTP induction was investigated, while hippocampal melatonin synthesis had been inhibited. The melatonin synthesis was inhibited by AANAT-siRNA administration, and LTP was induced using in vivo field potential electrophysiological recording. Animals were divided into 5 groups: Intact, vehicle, siRNA, GnRH and siRNA+GnRH. All animals, except intact group, experienced the stereotaxic surgery and intra-hippocampal cannulation to receive vehicle agent, AANAT siRNA (0.5 µg/hip), GnRH (1 ng/rat), and AANAT siRNA+GnRH. The recognition memory was assessed by Novel object recognition test. The field potential electrophysiology experiment was conducted by stimulating the Schaffer collateral pathway, and LTP induction was carried out through high-frequency stimulation (HFS). After recording, animals' brain was isolated and quickly frozen for further hippocampal melatonin levels measurement by LC-MS and AANAT mRNA levels by qRT-PCR. GnRH injection in the hippocampus increased local AANAT-mRNA expression and melatonin levels. GnRH-treated animals displayed higher LTP amplitude compared to intact, vehicle and siRNA groups. While the reduction in hippocampal melatonin levels by AANAT-siRNA inhibited LTP and impaired recognition memory, the GnRH prevented these adverse effects. The data suggests that GnRH have protective effects against AANAT-siRNA-induced LTP decline. The protective mechanism at least partially, may be related to the increased expression of local AANAT-mRNA.

Uncovering the protective potential of vanillic acid against traumatic brain injury-induced cognitive decline in male rats: Insights into underlying mechanisms.

Traumatic brain injury (TBI) is a significant contributor to global mortality and disability, and there is still no specific drug available to treat cognitive deficits in survivors. Vanillic acid (VA), a bioactive phenolic compound, has shown protective effects in various models of neurodegeneration; however, its impact on TBI outcomes remains elusive. Therefore, this study aimed to elucidate the possible role of VA in ameliorating TBI-induced cognitive decline and to reveal the mechanisms involved. TBI was induced using the Marmarou impact acceleration model to deliver an impact force of 300 g, and treatment with VA (50 mg/kg; P.O.) was initiated 30 minutes post-TBI. The cognitive performance, hippocampal long-term potentiation (LTP), oxidative stress markers, neurological function, cerebral edema, and morphological changes were assessed at scheduled points in time. TBI resulted in cognitive decline in the passive avoidance task, impaired LTP in the perforant path-dentate gyrus (PP-DG) pathway, increased hippocampal oxidative stress, cerebral edema, neurological deficits, and neuronal loss in the rat hippocampus. In contrast, acute VA administration mitigated all the aforementioned TBI outcomes. The data suggest that reducing synaptic plasticity impairment, regulating oxidative and antioxidant defense, alleviating cerebral edema, and preventing neuronal loss by VA can be at least partially attributed to its protection against TBI-induced cognitive decline.

Slow Release of Hydrogen Sulfide in CA1 Hippocampal Neurons Rescues Long-Term Synaptic Plasticity and Associativity in an Amyloid-ß Induced Model of Alzheimer's Disease.

Background: Impairment of synaptic plasticity along with the formation of amyloid-ß (Aß) plaques and tau-protein neurofibrillary tangles have been associated with Alzheimer's disease (AD). Earlier studies with rat and mouse hippocampal slices have revealed the association of AD with the absence of synthesis of memory related proteins leading to impairment in cognitive functions. The role of hydrogen sulfide (H2S), a gaseous neurotransmitter, has been gaining attention as a neuroprotective agent. However, its role in AD-like conditions has not been studied so far. Objective: To study the neuroprotective role of H2S in AD conditions using rat hippocampal slices and the organic molecule GYY4137, a slow releasing H2S donor. Methods: Electrophysiological recordings were carried out in rat hippocampal slices to look into the impairment of LTP, a cellular correlate of memory. The Aß42 peptide was bath-applied to mimic AD-like conditions and checked for both late-LTP and synaptic tagging and capture (STC) mechanisms of the synapses. GYY4137 was applied to look into its neuroprotective role at different stages during the recording of fEPSP. Results: There has been a steady decline in the plasticity properties of the synapses, in the form of late-LTP and STC, after the application of Aß42 peptide in the hippocampal slices. However, application of GYY4137 rescued these conditions in vitro. Conclusions: GYY4137, with its slow release of H2S, could possibly act as a therapeutic agent in cognitive dysfunctions of the brain, mainly AD.

Anisomycin alleviates cognitive impairments and pathological features in 3xTg-AD mice.

Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Anisomycin is a pyrrolidine antibiotic isolated from Streptomyces griseolus, which is an efficient anti-inflammatory agent that functions both in vivo and in vitro. However, it is not clear whether anisomycin can exert neuroprotective effect in AD. In the present study, anisomycin was intragastrically administrated to female triple-transgenic AD (3xTg-AD) model mice, then Morris water maze test was used to observe the long-term spatial memory of mice, the in vivo hippocampal field potential recording was performed to evaluate the synaptic plasticity, the Western blot and immunofluorescence were employed to detect pathological changes, and the bioinformatics analysis was used to predict the potential target of anisomycin exerting effects in AD. The results showed that anisomycin ameliorated the long-term spatial memory deficits, improved LTP depression and increased the expression of PSD-95, reduced the Aß and tau pathologies, and alleviated the activation of microglia and astrocytes in the brains of 3xTg-AD mice. In addition, the results from bioinformatics analysis showed that the potential target of anisomycin focused on inflammatory pathway. These results indicated that anisomycin exerts neuroprotective effects in 3xTg-AD mice by alleviating neuroinflammation, but the potential mechanism of anisomycin exerting neuroprotective effects needs to be further investigated.

Synaptic sensitization in the anterior cingulate cortex sustains the consciousness of pain via synchronized oscillating electromagnetic waves.

A recent report showed that experiencing pain requires not only activities in the brain, but also the generation of electric fields in a defined area of the anterior cingulate cortex (ACC). The present manuscript presents evidence that electromagnetic (EM) waves are also necessary. Action potentials (APs) encoding information about an injury stimulate thousands synapses on pyramidal neurons within the ACC resulting in the generation of synchronized oscillating (EM) waves and the activation of NMDA receptors. The latter induces a long-term potentiation (LTP) in the pyramidal dendrites that is necessary to experience both neuropathic and visceral pain. The LTP sensitizes transmission across the synapses that sustains the duration of the waves and the pain, EM waves containing information about the injury travel throughout the brain and studies using transcranial stimulation indicate that they can induce NMDA-mediated LTP in distant neuronal circuits. What is ultimately experienced as pain depends on the almost instantaneous integration of information from numerous neuronal centers, such as the amygdala, that are widely separated in the brain. These centers also generate EM waves and I propose that the EM waves from these centers interact to rapidly adjust the intensity of the pain to accommodate past and present circumstances. Where the waves are transformed into a consciousness of pain is unknown. One possibility is the mind which, according to contemporary theories, is where conscious experiences arise. The hypothesis can be tested directly by blocking the waves from the ACC. If correct, the waves would open new avenues of research into the relationship between the brain, consciousness, and the mind.

Involvement of a lateral entorhinal cortex engram in episodic-like memory recall.

Episodic memory relies on the entorhinal cortex (EC), a crucial hub connecting the hippocampus and sensory processing regions. This study investigates the role of the lateral EC (LEC) in episodic-like memory in mice. Here, we employ the object-place-context-recognition task (OPCRT), a behavioral test used to study episodic-like memory in rodents. Electrophysiology in brain slices reveals that OPCRT specifically induces a shift in the threshold for the induction of synaptic plasticity in LEC superficial layer II. Additionally, a dual viral system is used to express chemogenetic receptors coupled to the c-Fos promoter in neurons recruited during the learning. We demonstrate that the inhibition of LEC neurons impairs the performance of the mice in the memory task, while their stimulation significantly facilitates memory recall. Our findings provide evidence for an episodic-like memory engram in the LEC and emphasize its role in memory processing within the broader network of episodic memory.

Impaired hippocampal plasticity associated with loss of recycling endosomal SLC9A6/NHE6 is ameliorated by the TrkB agonist 7,8-dihydroxyflavone.

Proper maintenance of intracellular vesicular pH is essential for cargo trafficking during synaptic function and plasticity. Mutations in the SLC9A6 gene encoding the recycling endosomal pH regulator (Na+, K+)/H+ exchanger isoform 6 (NHE6) are causal for Christianson syndrome (CS), a severe form of X-linked intellectual disability. NHE6 expression is also downregulated in other neurodevelopmental and neurodegenerative disorders, such as autism spectrum disorder and Alzheimer's disease, suggesting its dysfunction could contribute more broadly to the pathophysiology of other neurological conditions. To understand how ablation of NHE6 function leads to severe learning impairments, we assessed synaptic structure, function, and cellular mechanisms of learning in a novel line of Nhe6 knockout (KO) mice expressing a plasma membrane-tethered green fluorescent protein within hippocampal neurons. We uncovered significant reductions in dendritic spines density, AMPA receptor (AMPAR) expression, and AMPAR-mediated neurotransmission in CA1 pyramidal neurons. The neurons also failed to undergo functional and structural enhancement during long-term potentiation (LTP). Significantly, the selective TrkB agonist 7,8-dihydroxyflavone restored spine density as well as functional and structural LTP in KO neurons. TrkB activation thus may act as a potential clinical intervention to ameliorate cognitive deficits in CS and other neurodegenerative disorders.

TMCO1 promotes ferroptosis and ECM deposition in glaucomatous trabecular meshwork via ERK1/2 signaling.

Glaucoma, a leading cause of global blindness, is marked by irreversible retinal ganglion cells (RGCs) loss, elevated intraocular pressure (IOP), and extracellular matrix (ECM) deposition in the trabecular meshwork (TM). Transmembrane and coiled-coil domain protein 1 (TMCO1), implicated in calcium regulation, has potential links to primary open-angle glaucoma (POAG). Ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, is also observed in glaucoma. This study investigates the role of TMCO1 in POAG, focusing on its involvement in TM ECM deposition via ferroptosis induction and ERK1/2 phosphorylation inhibition. In both in vivo and in vitro models, we demonstrated that dexamethasone (DEX) stimulation upregulates TMCO1, leading to increased ECM deposition and ferroptosis in human trabecular meshwork cells (HTMCs). Furthermore, treatment with ferrostatin-1 (Fer-1), a ferroptosis inhibitor, significantly reduced ECM deposition and ferroptosis in HTMCs. These findings establish TMCO1 as a critical regulator of ferroptosis and ECM deposition through the ERK/MAPK pathway, positioning it as a promising therapeutic target for glaucoma.

Lasting effects of transcranial direct current stimulation on the inducibility of synaptic plasticity by paired-associative stimulation in humans.

BACKGROUND: Transcranial direct current stimulation (tDCS) is capable of eliciting changes in cortical neuroplasticity. Increasing duration or repetition of tDCS during the after-effects of a first stimulation has been hypothesized to enhance efficacy. Computational models suggest sequential stimulation patterns with changing polarities to further enhance effects. Lasting tDCS effects on neural plasticity are of great importance for clinical applications. OBJECTIVE: The study systematically examined the influence of different tDCS paradigms on long term potentiation (LTP)-like plasticity in humans, focusing on stimulation duration, repetition frequency and sequential combinations of changing polarities as the underlying characteristics. METHODS: Amplitude changes of motor evoked potentials (MEP) were measured in response to paired associative stimulation (PAS) 6 h after application of different tDCS protocols. In total, 36 healthy participants completed the study, randomised into three groups with different stimulation protocols (N = 12 each). RESULTS: tDCS was able to display lasting modulatory effects on the inducibility of LTP-like plasticity in the human motor cortex 6 h after stimulation. TDCS with the anode on primary motor cortex significantly increased MEP amplitudes following PAS induction. Further analyses highlighted single stimulation block duration to be of higher importance than repetitive protocols for efficacy of effects. CONCLUSIONS: tDCS is capable of inducing lasting changes in the brain's capability to interact with future stimuli. Especially, effects on the inducibility of LTP-like plasticity might only be detectable with specific tests such as PAS and might otherwise be overlooked. Refined tDCS protocols should focus on higher current and duration of single stimulations instead of implementing complex repetitive schedules.

Effects of prolonged escitalopram administration on long-term potentiation within the hippocampal CA1 area in rats under predictable and unpredictable chronic mild stress.

Exposure to chronic stress impairs memory. Also, escitalopram's impact on memory remains paradoxical. Therefore, this study examined how prolonged escitalopram administration affects input-output (I/O) functions, paired-pulse ratio (PPR), and long-term potentiation (LTP) in the hippocampal CA1 area in rats that underwent predictable and unpredictable chronic mild stress (PCMS and UCMS, respectively). Male rats were randomly assigned to different groups of control (Co), sham (Sh), PCMS and UCMS (PSt and USt, respectively; 2 h/day, for 21 consecutive days), escitalopram (Esc; 10 mg/kg, i.p., for 21 days), as well as PCMS and UCMS with escitalopram (PSt-Esc and USt-Esc, respectively). The fEPSP slope, amplitude, and area under the curve (AUC) were assessed in the hippocampal CA1 area using I/O functions, PP responses, and LTP. Serum corticosterone (CORT) levels were quantified in all experimental animals. The slope, amplitude, and AUC of fEPSP in the I/O functions, and all three PP phases prior and subsequent to LTP induction significantly declined in the USt and PSt groups. Escitalopram significantly enhanced these parameters in the PSt-Esc, but not in the USt-Esc group. Serum CORT levels corroborated the electrophysiological findings among experimental groups. Both PCMS and UCMS impaired neural excitability, neurotransmission, and memory within the hippocampal CA1 area. Escitalopram improved memory impairment only under PCMS, potentially attributed to reduced serum CORT levels. However, no influence on neural excitability, neurotransmission, and memory was observed under UCMS. This suggests different escitalopram doses might be required to ameliorate simultaneous mechanisms in response to various types of chronic mild stress.

A computational model elucidating mechanisms and variability in theta burst stimulation responses.

Theta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation (rTMS) with unknown underlying mechanisms and highly variable responses across subjects. To investigate these issues, we developed a simple computational model. Our model consisted of two neurons linked by an excitatory synapse that incorporates two mechanisms: short-term plasticity (STP) and spike-timing-dependent plasticity (STDP). We applied a variable-amplitude current through I-clamp with a TBS time pattern to the pre- and post-synaptic neurons, simulating synaptic plasticity. We analyzed the results and provided an explanation for the effects of TBS, as well as the variability of responses to it. Our findings suggest that the interplay of STP and STDP mechanisms determines the direction of plasticity, which selectively affects synapses in extended neurons and underlies functional effects. Our model describes how the timing, number, and intensity of pulses delivered to neurons during rTMS contribute to induced plasticity. This not only successfully explains the different effects of intermittent TBS (iTBS) and continuous TBS (cTBS), but also predicts the results of other protocols such as 10 Hz rTMS. We propose that the variability in responses to TBS can be attributed to the variable span of neuronal thresholds across individuals and sessions. Our model suggests a biologically plausible mechanism for the diverse responses to TBS protocols and aligns with experimental data on iTBS and cTBS outcomes. This model could potentially aid in improving TBS and rTMS protocols and customizing treatments for patients, brain areas, and brain disorders.

Continuous exercise training rescues hippocampal long-term potentiation in the VPA rat model of Autism: Uncovering sex-specific effects.

Long-term potentiation (LTP) impairment has been reported in many studies of autistic models. The aim of the present study was to investigate the effects of interval training (IT) and continuous training (CT) exercises on LTP in the hippocampal dentate gyrus (DG) neurons of valproic acid (VPA) rat model of autism. To induce an autism-like model, pregnant rats were injected 500 mg/kg NaVPA (intraperitoneal) on the embryonic day 12.5. IT and CT aerobic exercises started on postnatal day 56 in the offspring. Four weeks after IT and/or CT exercises, the offspring were urethane-anesthetized and placed into a stereotaxic apparatus for surgery, electrode implantation, and field potential recording. In the DG region, excitatory post synaptic potentials (EPSP) slope and population spike (PS) amplitude were measured. Sex differences in LTP were evident for control rats but not for VPA-exposed offspring. LTP was significantly smaller in VPA-exposed male offspring compared with control male rats. In contrast to males, there was no difference between VPA-exposed female offspring and control female rats. Interestingly, we observed a sex difference in the response to exercise between VPA-exposed male and female offspring. CT exercise training (but not IT) increased LTP in VPA-exposed male offspring. Both IT and CT exercise trainings had no effect on intact LTP in VPA-exposed female offspring. Our work suggests that there may be differences in the benefits of exercise interventions based on sex, and CT exercise training could be more beneficial for LTP improvements.

Interference with glutamate antiporter system xc - enables post-hypoxic long-term potentiation in hippocampus.

Our group previously showed that genetic or pharmacological inhibition of the cystine/glutamate antiporter, system xc -, mitigates excitotoxicity after anoxia by increasing latency to anoxic depolarization, thus attenuating the ischaemic core. Hypoxia, however, which prevails in the ischaemic penumbra, is a condition where neurotransmission is altered, but excitotoxicity is not triggered. The present study employed mild hypoxia to further probe ischaemia-induced changes in neuronal responsiveness from wild-type and xCT KO (xCT-/-) mice. Synaptic transmission was monitored in hippocampal slices from both genotypes before, during and after a hypoxic episode. Although wild-type and xCT-/- slices showed equal suppression of synaptic transmission during hypoxia, mutant slices exhibited a persistent potentiation upon re-oxygenation, an effect we termed 'post-hypoxic long-term potentiation (LTP)'. Blocking synaptic suppression during hypoxia by antagonizing adenosine A1 receptors did not preclude post-hypoxic LTP. Further examination of the induction and expression mechanisms of this plasticity revealed that post-hypoxic LTP was driven by NMDA receptor activation, as well as increased calcium influx, with no change in paired-pulse facilitation. Hence, the observed phenomenon engaged similar mechanisms as classical LTP. This was a remarkable finding as theta-burst stimulation-induced LTP was equivalent between genotypes. Importantly, post-hypoxic LTP was generated in wild-type slices pretreated with system xc - inhibitor, S-4-carboxyphenylglycine, thereby confirming the antiporter's role in this phenomenon. Collectively, these data indicate that system xc - interference enables neuroplasticity in response to mild hypoxia, and, together with its regulation of cellular damage in the ischaemic core, suggest a role for the antiporter in post-ischaemic recovery of the penumbra.

The Unexpected Role of the Endothelial Nitric Oxide Synthase at the Neurovascular Unit: Beyond the Regulation of Cerebral Blood Flow.

Nitric oxide (NO) is a highly versatile gasotransmitter that has first been shown to regulate cardiovascular function and then to exert tight control over a much broader range of processes, including neurotransmitter release, neuronal excitability, and synaptic plasticity. Endothelial NO synthase (eNOS) is usually far from the mind of synaptic neurophysiologists, who have focused most of their attention on neuronal NO synthase (nNOS) as the primary source of NO at the neurovascular unit (NVU). Nevertheless, the available evidence suggests that eNOS could also contribute to generating the burst of NO that, serving as volume intercellular messenger, is produced in response to neuronal activity in the brain parenchyma. Herein, we review the role of eNOS in both the regulation of cerebral blood flow and of synaptic plasticity and discuss the mechanisms by which cerebrovascular endothelial cells may transduce synaptic inputs into a NO signal. We further suggest that eNOS could play a critical role in vascular-to-neuronal communication by integrating signals converging onto cerebrovascular endothelial cells from both the streaming blood and active neurons.

Genetic mechanisms for impaired synaptic plasticity in schizophrenia revealed by computational modeling.

Schizophrenia phenotypes are suggestive of impaired cortical plasticity in the disease, but the mechanisms of these deficits are unknown. Genomic association studies have implicated a large number of genes that regulate neuromodulation and plasticity, indicating that the plasticity deficits have a genetic origin. Here, we used biochemically detailed computational modeling of postsynaptic plasticity to investigate how schizophrenia-associated genes regulate long-term potentiation (LTP) and depression (LTD). We combined our model with data from postmortem RNA expression studies (CommonMind gene-expression datasets) to assess the consequences of altered expression of plasticity-regulating genes for the amplitude of LTP and LTD. Our results show that the expression alterations observed post mortem, especially those in the anterior cingulate cortex, lead to impaired protein kinase A (PKA)-pathway-mediated LTP in synapses containing GluR1 receptors. We validated these findings using a genotyped electroencephalogram (EEG) dataset where polygenic risk scores for synaptic and ion channel-encoding genes as well as modulation of visual evoked potentials were determined for 286 healthy controls. Our results provide a possible genetic mechanism for plasticity impairments in schizophrenia, which can lead to improved understanding and, ultimately, treatment of the disorder.

The interaction between cannabinoids and long-term synaptic plasticity: A survey on memory formation and underlying mechanisms.

Synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), is an essential phenomenon in memory formation as well as maintenance along with many other cognitive functions, such as those needed for coping with external stimuli. Synaptic plasticity consists of gradual changes in the biochemistry and morphology of pre- and postsynaptic neurons, particularly in the hippocampus. Consuming marijuana as a primary source of exocannabinoids immediately impairs attention and working memory-related tasks. Evidence regarding the effects of cannabinoids on LTP and memory is contradictory. While cannabinoids can affect a variety of specific cannabinoid receptors (CBRs) and nonspecific receptors throughout the body and brain, they exert miscellaneous systemic and local cerebral effects. Given the increasing use of cannabis, mainly among the young population, plus its potential adverse long-term effects on learning and memory processes, it could be a future global health challenge. Indeed, the impact of cannabinoids on memory is multifactorial and depends on the dosage, timing, formula, and route of consumption, plus the background complex interaction of the endocannabinoids system with other cerebral networks. Herein, we review how exogenously administrated organic cannabinoids, CBRs agonists or antagonists, and endocannabinoids can affect LTP and synaptic plasticity through various receptors in interaction with other cerebral pathways and primary neurotransmitters.

Selegiline Improves Cognitive Impairment in the Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurological disorder characterized by cognitive decline. This study was undertaken to evaluate the effects of selegiline (SEL) against AD-induced cognitive deficits and explore the possible involved mechanisms. AD was induced by unilateral intracerebroventricular (U-ICV) injection of 5 µg of amyloid beta1-42 (Aß1-42), and oral administration of SEL (0.5 mg/kg/day) was performed for 30 consecutive days. Aß injection resulted in spatial cognitive decline, as demonstrated by a decrease in the time spent in the target zone on the probe day (P < 0.01) in the Barnes maze test (BMT). This spatial cognitive decline was associated with disrupted synaptic plasticity, as indicated by reductions in both components of hippocampal long-term potentiation (LTP), namely population spike amplitude (P < 0.001) and field excitatory postsynaptic potential (P < 0.001). On the other hand, the injection of Aß resulted in oxidative stress by decreasing total thiol group (TTG) content and increasing malondialdehyde (MDA) levels in the rat plasma (P < 0.001). Additionally, the number of healthy cells in the hippocampal dentate gyrus (DG) and CA1 regions was reduced in AD rats (P < 0.001). However, oral administration of SEL improved spatial cognitive decline in the Aß-induced AD rats. The results suggest that improvement of neuroplasticity deficiency, regulation of oxidant/antioxidant status, and suppression of neuronal loss by SEL may be the mechanisms underlying its beneficial effect against AD-related spatial cognitive impairment.

L-type Ca2+ channel activation of STIM1-Orai1 signaling remodels the dendritic spine ER to maintain long-term structural plasticity.

Learning and memory require coordinated structural and functional plasticity at neuronal glutamatergic synapses located on dendritic spines. Here, we investigated how the endoplasmic reticulum (ER) controls postsynaptic Ca2+ signaling and long-term potentiation of dendritic spine size, i.e., sLTP that accompanies functional strengthening of glutamatergic synaptic transmission. In most ER-containing (ER+) spines, high-frequency optical glutamate uncaging (HFGU) induced long-lasting sLTP that was accompanied by a persistent increase in spine ER content downstream of a signaling cascade engaged by N-methyl-D-aspartate receptors (NMDARs), L-type Ca2+ channels (LTCCs), and Orai1 channels, the latter being activated by stromal interaction molecule 1 (STIM1) in response to ER Ca2+ release. In contrast, HFGU stimulation of ER-lacking (ER-) spines expressed only transient sLTP and exhibited weaker Ca2+ signals noticeably lacking Orai1 and ER contributions. Consistent with spine ER regulating structural metaplasticity, delivery of a second stimulus to ER- spines induced ER recruitment along with persistent sLTP, whereas ER+ spines showed no additional increases in size or ER content in response to sequential stimulation. Surprisingly, the physical interaction between STIM1 and Orai1 induced by ER Ca2+ release, but not the resulting Ca2+ entry through Orai1 channels, proved necessary for the persistent increases in both spine size and ER content required for expression of long-lasting late sLTP.